SIAH2 is a novel target in breast and other cancers; in a study on advanced and metastatic breast cancer, Siewertz van Reesama et al found that both SIAH and EGFR outperform standard breast cancer biomarkers in predicting advanced stages of metastasis SIAH2 is a downstream member of the RAS pathway, where it is required for signal transduction. SIAH2 expression acts as a sign of activation of the RAS pathway, and its deficiency has been found to reduce MAPK signaling. SIAH2 has been found to be overexpressed in invasive breast cancers versus ductal carcinomas and normal tissue, where it may cause aberrant activation of the ERK pathway, encouraging proliferation and simultaneous dysregulation of apoptotic signaling. In immunohistochemistry, SIAH2 has both cytoplasmic and nuclear positivity in a majority of tissues. References: EBioMedicine. 2016 Sep;11:183-198, PMID: 27569656, J Natl Cancer Inst. 2008 Nov 19;100(22):1606-29, PMID: 19001609; Oncology Reports 36, no. 3 (2016): 1301-1312, DOI: 10.3892/or.2016.4976;